Ivan Marinkovic, M.D.
EXPERIMENTAL STUDIES
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Daniel Strbian, M.D., Ph.D. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland; and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Eric Pedrono, M.Sc. Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Olga Y. Vekovischeva, Ph.D. Department of Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
Shashank Shekhar, M.D. Department of Neurology, Helsinki University Central Hospital, and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Aysan Durukan, M.D. Department of Neurology, Helsinki University Central Hospital, and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Esa R. Korpi, M.D., Ph.D. Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
Usama Abo-Ramadan, Ph.D. Department of Neurology, Helsinki University Central Hospital, and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland
Turgut Tatlisumak, M.D., Ph.D. Department of Neurology, Helsinki University Central Hospital, and Experimental MRI Laboratory, Biomedicum Helsinki, Helsinki, Finland Reprint requests: Daniel Strbian, M.D., Ph.D., Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, PL 340, 00290 Helsinki, Finland. Email:
[email protected] Received, November 24, 2008. Accepted, April 24, 2009. Copyright © 2009 by the Congress of Neurological Surgeons
DECOMPRESSIVE CRANIECTOMY FOR INTRACEREBRAL HEMORRHAGE OBJECTIVE: Intracerebral hemorrhage (ICH) has a high mortality rate and leaves most survivors disabled. The dismal outcome is mostly due to the mass effect of hematoma plus edema. Major clinical trials show no benefit from surgical or medical treatment. Decompressive craniectomy has, however, proven beneficial for large ischemic brain infarction with massive swelling. We hypothesized that craniectomy can improve ICH outcome as well. METHODS: We used the model of autologous blood injection into the basal ganglia in rats. After induction of ICH and then magnetic resonance imaging, animals were randomly allocated to groups representing no craniectomy (n 10) or to craniectomy at 1, 6, or 24 hours. A fifth group without ICH underwent craniectomy only. Neurological and behavioral outcomes were assessed on days 1, 3, and 7 after ICH induction. Furthermore, terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells were counted. RESULTS: After 7 days, compared with the ICH + no craniectomy group, all craniectomy groups had strikingly lower mortality (P 0.01), much better neurological outcome (P 0.001), and more favorable behavioral outcome. A trend occurred in the ICH + no craniectomy group toward more robust apoptosis. CONCLUSION: Decompressive craniectomy performed up to 24 hours improved outcome after experimental ICH, with earlier intervention of greater benefit. KEY WORDS: Decompressive craniectomy, Intracerebral hemorrhage, Magnetic resonance imaging, Mortality, Rat Neurosurgery 65:780–786, 2009
DOI: 10.1227/01.NEU.0000351775.30702.A9
I
n Western countries, intracerebral hemorrhage (ICH) accounts for 10% to 15% of all strokes, and the percentage in Asian and black populations is even higher (20%–30%) (20). ICH is associated with high mortality, with 60% to 70% of the patients surviving through the first month but only 40% to 50% through the first year (12, 20), many of them with severe disabilities. Poor outcome results both from early and delayed changes after ICH. After the hemorrhagic event, direct tissue destruction and dissection of blood occurs, followed by edema formation. These changes are complicated by the mass effect of the growing ABBREVIATIONS: ICH, intracerebral hemorrhage; ICP, intracranial pressuree; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.neurosurgery-online.com).
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hematoma (in 40% of patients within 20 h) (1), leading to increased intracranial pressure (ICP) and to disruption and displacement of brain structures. A role for mast cells has recently emerged in mediating edema and hematoma growth under experimental conditions (18). Delayed damage is mediated by toxins associated with blood breakdown products, thrombin, and inflammation (5, 21). Furthermore, necrosis, apoptosis (7), excitotoxicity (15), and disruption of the blood-brain barrier (14) all contribute to brain damage. The counterpart to emergency thrombolysis treatment of acute ischemic stroke is hemostatic therapy with the aim of cessation of hematoma growth. Thus far, ε-aminocaproic acid, aprotinin, and tranexamic acid have been tested, albeit unsuccessfully (8, 13). Recently, recombinant activated factor VII has reduced growth of hematoma volume but without improvement in survival or functional outcome (9), and surgical evacuation of ICH has not been beneficial (11).
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FIGURE 1. Representative T2-weighted images. Intracerebral hemorrhage (ICH) at the level of the basal ganglia in the right hemisphere at baseline (day 0), 72 hours (day 3), and 1 week (day 7) after ICH induction in early (ICH + craniectomy 1 hour), late (ICH + craniectomy 24 hours), or no craniectomy (ICH + no craniectomy) groups. Note the hyperintensity representing the brain edema.
To fight massive brain swelling and the consequences of increased ICP in patients with malignant ischemic brain infarction, decompressive craniectomy was first successfully introduced experimentally (3). Thereafter, its efficacy was evident in several clinical trials (19), and it has recently become part of routine ischemic stroke care. Decompressive craniectomy is a surgical procedure during which a part of the skull over the affected brain region is temporarily removed, providing extra space for brain swelling, reducing ICP, and alleviating mechanical damage to both nearby and remote brain structures. Because the mass effect of hematoma and brain swelling significantly contribute to poor outcome after ICH (4), we tested the hypothesis whether, in experimental ICH, decompressive craniectomy at 3 time points (Table 1) improves outcome. Performed up to 24 hours after ICH induction, it provided highly significant benefits in terms of reduced mortality and better neurological outcomes, as well as more favorable behavioral scores, showing that the earlier the procedure is performed, the better the outcome.
MATERIALS AND METHODS Animals Adult male Wistar rats (Harlan Nederland, Horst, The Netherlands), weighing 300 to 350 g, were anesthetized by an intraperitoneal injection of ketamine hydrochloride (Ketalar, 50 mg/kg; Parke-Davis, Stockholm,
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Sweden) and a subcutaneous injection of medetomidine hydrochloride (Domitor, 0.5 mg/kg; Orion, Espoo, Finland). These rats were randomly allocated to 5 groups (Table 1). Those having the crani ectomy at 6 and 24 hours after ICH induction were reanesthetized before the procedure. A PE-50 polyethylene tube was inserted into the left femoral artery for monitoring of blood pressure (Olli Blood Pressure Meter 533; Kone Oy, Espoo, Finland) and for obtaining blood for ICH induction. Rectal temperature was maintained at 37⬚C during the operation and magnetic resonance imaging with a heating blanket and a thermo-regulated heating lamp. Body weight was measured daily. Before and during the experiments, the rats were housed under diurnal lighting conditions and allowed free access to food and water. The animal research committee approved the study protocol.
ICH Model
To mimic ICH, we used the autologous whole blood injection model described elsewhere (17). The head of the anesthetized animal was fixed into a stereotaxic frame (Stoelting Co., Wood Dale, IL), and a midline scalp incision disclosed the calvaria of the skull. A burr hole, 1 mm in diameter, was drilled into the right side of the cranium, 0.2 mm anterior and 3.0 mm lateral to the bregma. A 27-gauge needle attached to a Hamilton syringe was inserted into the core of the right basal ganglia at 6.0-mm depth from the skull surface and subsequently lifted by 0.5 mm, thus producing a small pouch. Thereafter, 75 µL of freshly collected homologous arterial blood was injected slowly into the brain (2 µL/12 s), after which the needle was kept in place for 5 minutes. The burr hole was then sealed with bone wax, and the scalp was sutured. In a pilot project, we found a hematoma volume of 75 µL to have a mortality rate of approximately 50%, i.e., relevant to the clinical outcome.
Decompressive Craniectomy We used a decompressive craniectomy procedure as described in the experimental study with a decompressive craniectomy after malignant ischemic stroke (3). Under general anesthesia and after lidocaine application to the bony surface of the skull, a bone flap (0.9 0.5 cm) was created in the right temporal bone with a dental drill, and additional bone was removed down to the floor of the middle fossa under microscopic control with microscissors. The dura covering the frontal, parietal, and temporal lobes was then opened in a large cruciate incision. No cortical resection of the brain was evident (Fig. 1). At the end of this procedure, the temporalis muscle and skin flap were adapted and sutured in place. Instruments were kept sterilized, and sterile working conditions were maintained. Furthermore, the antibiotic ceftriaxone (Ceftriaxon Copyfarm, 50 mg/kg, Oxifarm Generics, Odense
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TABLE 1. Groups and study protocola ICH
MRI
ICH no craniectomy (n 20)
Group
X
X
ICH craniectomy 1-h (n 10)
X
X
ICH craniectomy 6-h (n 10)
X
ICH craniectomy 24-h (n 11)
X
Craniectomy-only (n 10) a
Craniectomy
Outcome scoring
Follow-up MRI
Day 1, 3, and 7
Day 3 and 7
1 h after ICH
Day 1, 3, and 7
Day 3 and 7
X
6 h after ICH
Day 1, 3, and 7
Day 3 and 7
X
24 h after ICH
Day 1, 3, and 7
Day 3 and 7
X
1 h after anesthesia
Day 1, 3, and 7
Day 3 and 7
ICH, intracerebral hemorrhage; MRI, magnetic resonance imaging.
S, Denmark) was administered subcutaneously immediately and 24 hours after craniectomy or ICH induction, and the analgesic buprenorphine (Temgesic, 0.05 mg/kg; Schering-Plough, Kenilworth, NJ) was administered subcutaneously 3 times daily during the first 48 hours.
Magnetic Resonance Imaging Magnetic resonance imaging studies were performed immediately after ICH induction and on days 3 and 7 using a 4.7-T scanner (PharmaScan; Bruker BioSpin, Ettlingen, Germany) with the use of a 90-mm shielded gradient capable of producing a maximum gradient amplitude of 300 mT/m with an 80-microsecond rise time. A linear birdcage radiofrequency coil with an inner diameter of 38 mm was used. After shimming and scout images, coronal T2*-weighted images encompassing the whole brain were acquired with a gradient echo sequence (repetition time, 350 ms; echo time, 10 ms; flip angle, 40; matrix size, 256 128; field of view, 40 40 mm; number of averages, 4; 14 slices; and slice thickness, 1 mm).
observed for positional passivity, trunk curl, trunk curl direction (right or left), and forelimb tension and flexion (for scoring, see Table; Supplemental Digital Content 1, http://links.lww.com/NEU/A240). After that, the animal was lowered to close above a wire grid, and visual placing, together with forepaw grasping of the wire, was evaluated. Next, the animal was allowed to grip the grid with its claws, a gentle horizontal backwards pull was applied, and grip strength was estimated. Forepaw flexibility was checked on a smooth surface. Then, the animal was allowed to grasp a horizontal beam by its forelimbs, and the grasping, together with the beam maneuver, was recorded. Thereafter, the animal was put into a viewing jar (a glass cylinder 10 cm in diameter) for 2 minutes, and its body position, spontaneous activity, and behavioral abnormalities related to body position were evaluated according to the scoring scale.
Tissue Handling and Terminal Deoxynucleotidyl Transferase dUTP Nick-End Labeling Staining
We calculated the percentage of hemispheric expansion from T2*-weighted images as described previously (18). In brief, we calculated the volumetric increase in the ICH hemisphere compared with that of the intact hemisphere (percentage of hemispheric expansion [(right hemisphere volume/left hemisphere volume) 1] 100).
On day 7 after ICH induction, each animal received an overdose (60 mg) of sodium pentobarbital (Mebunat; Orion) and underwent cardiac perfusion fixation with ice-cold 4% paraformaldehyde. Thereafter, the brains were quickly collected and placed in 10% formalin, embedded in paraffin blocks, and cut into 4-µm slices. Two slices cut at the site of injection were stained with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) (In Situ Cell Death Detection Kit, Fluorescein; Roche, Mannheim, Germany) for detecting DNA fragmentation and apoptotic bodies. The TUNEL assay was performed according to the manufacturer’s instructions. Slices stained with TUNEL were assessed with a light microscope (Axiovert; Carl Zeiss, Hallbergmoos, Germany). TUNEL-positive cells were counted in the whole hemorrhagic (right) hemisphere (including clot) and in the healthy contralateral hemisphere. Thereafter, we calculated the TUNEL index, which is a count of TUNEL-positive cells in the right hemisphere divided by the count of TUNEL-positive cells in the left hemisphere.
Neurological Evaluation and Mortality
Statistical Analyses
We scored neurological performance at days 1, 3, and 7 after ICH induction on an 8-point scale (0, no deficit; 1, contralateral forepaw paresis; 2, 1 plus decreased resistance to lateral push, yet no circling; 3, 2 plus circling to the contralateral side; 4, falling to the contralateral side; 5, rolling; 6, no spontaneous walking, with a depressed level of consciousness; and 7, death).
Data are expressed as mean standard error of the mean for parametric data, as medians (first and third quartiles) for nonparametric data, or as proportions. Repeated measurements were analyzed with 2-way repeated-measures analysis of variance followed by the HolmSidak post hoc test to detect changes over time or between groups. Changes in behavioral outcome related to the day of follow-up were identified for each group with the Friedman 1-way repeated-measures analysis of variance on ranks, followed by a Dunn post hoc test. The same test served to identify intergroup differences in behavioral outcome for a specific time point. Mortality rates were analyzed with the χ2 test followed by the Marascuilo procedure (6) for comparing multiple proportions and were confirmed by multiple Fisher exact tests. A 2-tailed P value of less than 0.05 was considered significant.
Hematoma Volume Hematoma volumes were calculated immediately and 3 and 7 days after ICH induction on the basis of their specific signal intensity on T2*weighted images. The boundaries of the hematoma were tracked manually (Paravision; Bruker BioSpin, Ettlingen, Germany), the surface area of hematoma on each brain slice was multiplied by the slice thickness, and the values were summed to yield total hematoma volume.
Hemispheric Expansion
Behavioral Evaluation The assessment of behavioral status based on the SHIRPA protocol (16) was performed blindly from video records collected on days 1, 3, and 7 after ICH. Evaluation started with a startle reflex test by a sudden hand-clap 15 cm above the rat’s head. Then the animal was grasped gently by the tail, held 30 cm above the bench top, and
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craniectomy group, 0% in the ICH + craniectomy 1-hour group, 10% in the ICH + craniectomy 6-hour group, and 0% in the craniectomy-only group. In the ICH + craniectomy 24-hour group, 3 animals (27%) died before craniectomy, but no more deaths occurred after craniectomy (Fig. 2). Post hoc analysis revealed a significant survival difference between the ICH + no craniectomy group and the ICH + craniectomy 1-hour group, the ICH + craniectomy 24-hour group, and the craniectomyonly group (for all 3, P 0.01).
Neurological Scores Compared with the ICH + no craniectomy group, all craniectomy groups had significantly better (P 0.001) neurological scores over time (Table 2). Animals in the craniectomy-only group all scored 0 (normal) at each time point.
Behavioral Outcome All behavioral data are presented in Table 3. We observed the most favorable outcome in the craniectomy-only group. During the follow-up, the ICH + craniectomy 1-hour group improved in 5 tests, the ICH + craniectomy 6-hour group improved in 2 tests, and the ICH + craniectomy 24-hour group improved in 1 test, whereas the ICH + no craniectomy group deteriorated in 3 tests (Table 3, middle column). The craniectomy-only group maintained a stable positive outcome throughout the entire follow-up period.
FIGURE 2. Mortality after intracerebral hemorrhage (ICH). The graph shows percentage of survivors for each group per time of death. Color arrows show the time of craniectomy. As can be seen from the graph, all (3) animals that died in the ICH + craniectomy 24-hour group did so before craniectomy was performed, with no further deaths thereafter. No death occurred in the craniectomy-only group.
RESULTS Physiological Parameters
ICH Volume and Hemispheric Expansion
No significant difference appeared in mean arterial blood pressure values (P 0.70, data not shown) nor in rectal temperature values (P 0.27, data not shown) among different time points within and among the groups. For days 3 and 7 (final day), a significantly (P 0.001) smaller loss of body weight occurred in the craniectomy-only group than in any other group. At day 3, the body weight loss in the ICH + no craniectomy group was significantly (P 0.05) smaller than that in the ICH + craniectomy 1-hour group.
Importantly, no difference appeared in the baseline ICH volumes among the groups (P 0.45). Figure 3 shows temporal changes in ICH volumes and Figure 4 shows changes in hemispheric expansions. No ICH or hemispheric expansion was evident in the craniectomy-only group.
TUNEL Staining The difference in the number of TUNEL-positive cells among the study groups did not reach statistical significance (P 0.054). The highest values calculated for the TUNEL index were in the ICH + no-craniectomy group, 6.4 (4.7, 21.0), and in the ICH + craniectomy 6-hour group, 8.3 (4.2, 27.9), whereas the lowest value, 2.5 (2.2, 2.6), was in the craniectomy-only group.
Mortality A highly significant difference emerged in mortality among the groups (P 0.001) (Fig. 2), being 45% in the ICH + no
TABLE 2. Neurological scoresa Group
Day 1 M
25%
Day 3 75%
M
25%
Day 7 75%
M
25%
75%
ICH no craniectomy
2
1
3
2.5
1
7
1.5
1
7
ICH craniectomy 1-h
1
1
1
1b
1
1
0b
0
0
ICH craniectomy 6-h
1
1
2
1b
0
1
0b
0
1
ICH craniectomy 24-h
1
1
1.25
1b
0.75
1
0b
0
0
a
M, median; 25% and 75%, first and third quartile. Significant difference (P 0.01) compared with the ICH no craniectomy group. No other intergroup significance was detected; the analysis was done without dead animals (n 3), which occurred in the ICH craniectomy 24-h group before craniectomy was performed. Animals in the craniectomy-only group all scored 0 (normal) for each time point. b
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TABLE 3. Outcome of behavioral testsa Test or posture
Change over time
Status at day 3
Startle reflex
NS
NS
Positional passivity (held by tail)
NS
NS
Trunk curl (held by tail)
NS
NS
Trunk direction
NS
NS
Visual placing response
↑ ICH-DC 24-h
NS
Forelimb extension and tension for R and L limb
NS
NS
Forepaw grasping for R and L limb
NS
NS
Grip strength for R and L limb
↑ ICH-DC 6-h
L: DC only ICH-DC 6-h; ICH-DC 24-h; ICH only
Smooth touch reflex for R and L limb
NS
L: DC only ICH-DC 6-h
Body position in viewing jarb
↑ ICH-DC 1-h; ↑ ICH-DC 6-h
NS
Spontaneous activity in viewing jar
NS
NS
Head position in viewing jar
NS
NS
Forelimb support
↑ ICH-DC 1-h
NS
Catatonia-like behavior in viewing jar
↑ ICH-DC 1-h
NS
Forelimb abnormal position in viewing jar
↓ ICH only; ↑ ICH-DC 1-h
DC only; ICH-DC 1-h; ICH-DC 6-h ICH only
Forelimb stereotypic position in viewing jar
NS
NS
Head stereotypic position in viewing jar
NS
NS
Stereotypic jaw-motion in viewing jar
↓ ICH only
NS
Stereotypic rotation in viewing jar
NS
NS
Falling to the side in viewing jar
NS
NS
Posture abnormalities in viewing jar
↑ ICH-DC 1-h; ↓ ICH only
All better than ICH
Beam maneuver
NS
Missing data
Forepaw grasping on beam
NS
DC only ICH-DC 6-h; ICH-DC 24-h
↑, improvement; ↓, worsening; , better than; NS, nonsignificant; ICH, intracerebral hemorrhage; DC, decompressive craniectomy; L, left; R, right. On day 7, statistical analysis identified only the following significant difference: the ICH-DC 1-h group had better outcome than did the ICH-DC 24-h group in the “body position in viewing jar” test.
a
b
Finally, the TUNEL index was 5.1 (3.1, 8.3) in the ICH + craniectomy 1-hour group and 5.1 (3.0, 14.3) in the ICH + craniectomy 24-hour group.
DISCUSSION ICH is a leading cause of death worldwide, with approximately 50% of 1-year survivors, many of them remaining severely disabled. Currently, no effective acute medical (9) or surgical (10) treatment exists, beyond general supportive measures. In the current study, we investigated whether decompressive craniectomy after experimental ICH leads to an outcome with a beneficial effect similar to that in malignant ischemic stroke. No similar external decompression approach has been reported, either for experimental or for clinical ICH. Our studies with an autologous blood injection model of ICH showed decompressive craniectomy to be of con-
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siderable benefit when performed before 24 hours (Fig. 2). Mortality was 45% in the ICH + no craniectomy group compared with no deaths in the ICH + craniectomy 1-hour group and 10% postcraniectomy mortality in the ICH + craniectomy 6-hour group. The latter finding would be influenced by administration of 2 doses of anesthesia during the rather short interval of 6 hours in this group. In the ICH + craniectomy 24-hour group, 3 (27%) animals died before the craniectomy, but none of the animals died thereafter. No deaths occurred in the craniectomy-only group, which served as a control for possible complications of the craniectomy, a rather invasive procedure. This result and the lack of any craniectomy in the ICH + no craniectomy group suggests that all mortality was due to ICH itself, and decompressive craniectomy was not a confounder. Mostly because of increased mortality, designated by the worst neurological score, the ICH + no craniectomy group had
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FIGURE 3. Temporal changes of intracerebral hemorrhage (ICH) volumes. Baseline ICH volumes among all groups were similar (P 0.45). Although the final ICH volume was slightly larger in the ICH + no craniectomy group than in any ICH + craniectomy group, this difference was not significant (P 0.065). ICH volume at day 3 was significantly larger in the ICH + no craniectomy group than in the ICH + craniectomy groups (P 0.001). DC, decompressive craniectomy; MRI, magnetic resonance imaging.
significantly worse neurological outcomes than did any ICH + craniectomy group (P 0.001) (Table 2). However, once an animal survived, it survived with a good outcome, which is expected in rodent disease models with long follow-up periods. Behavioral tests, which did not take mortality into account, showed better scores for the craniectomy-only group than for any other group (Table 3). Statistical analysis identified several intergroup differences at day 3 after ICH (Table 3). At day 7, except for 1 test score (posture abnormalities in a viewing jar), no other differences were observable besides those showing the best outcome for the craniectomy-only group. Nevertheless, we observed 1 important phenomenon in the dynamics of the behavioral outcome during follow-up: the ICH + craniectomy 1-hour group improved in 5 tests, the ICH + craniectomy 6-hour group improved in 2 tests, and the ICH + craniectomy 24-hour group improved in 1 test, whereas the ICH + nocraniectomy group failed to improve in any tests and deteriorated in 3 tests (Table 3). The craniectomy-only group showed consistently good scores throughout the follow-up. Baseline ICH volumes were similar in all groups (P 0.45) (Fig. 3). Statistical analysis identified a significant difference (P 0.048) in ICH volumes among the groups with different timing of craniectomy after allowing for effects of length of follow-up. All groups showed the same significance (P 0.001) for changes in ICH volumes during follow-up (Fig. 3), as the ICH volumes were gradually decreasing over time. However, ICH volume at day 3 was significantly larger in the ICH + no-craniectomy group than in any ICH + craniectomy group (P 0.001) (Fig. 3). Why the craniectomy groups ended with smaller ICH volumes at day 3 remains unclear. It is possible that decreased ICP
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FIGURE 4. Temporal changes of hemispheric expansion. The apparent smaller numbers of hemispheric expansions in the intracerebral hemorrhage (ICH) + no craniectomy group are misleading as dead animals are not included. These animals most likely died from massive brain swelling, but their magnetic resonance imaging data are unavailable. DC, decompressive craniectomy; MRI, magnetic resonance imaging.
reduced additional bleeding into the hematoma site and led to faster hematoma absorption. The final ICH volume was, however, only nonsignificantly larger in the ICH + no-craniectomy group than in the ICH + craniectomy groups (P 0.065) (Fig. 3). The rather minimal brain swelling in the ICH + no craniectomy group (Fig. 4) must be interpreted in view of the 45% mortality in this group. It may be assumed that the large number of fatalities in the ICH + no craniectomy group had resulted from massive brain swelling and increased ICP, because the mass effect of brain swelling and hematoma together with relative brain swelling (absolute brain swelling divided by hematoma volume) are known prognostic factors after human ICH (2, 4). Survivors in the ICH + no craniectomy group were thus probably those with less brain swelling. In sum, the data in this experimental model (Fig. 4) show that brain swelling reaching its maximum at day 3 after the ICH. Differences in TUNEL-positive cell counts among the groups (only surviving animals were included) did not reach statistical significance (P 0.054). The ICH + no craniectomy and the ICH + craniectomy 6-hour group had higher counts than did the craniectomy-only group. However, the rather high variation in TUNEL-positive cell counts does not let us draw firm conclusions as to the significance of these findings. One might only speculate that increased ICP in the ICH + no-craniectomy group (no craniectomy performed) was associated with higher mechanical pressure and decreased blood circulation in both nearby and remote brain regions. In the ICH + craniectomy 1-hour group, the reason for a low TUNEL-positive cell count may be the early lowering of the ICP and thus the reestablishment of homeostatic conditions before irreversible apoptotic pathways were activated. In the ICH + craniectomy 24-hour group, data from 3 animals found dead before the craniectomy
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were lacking, of course. Nevertheless, in this group, all animals with craniectomy had low TUNEL-positive cell counts. On the other hand, the ICH + craniectomy 6-hour group probably had the worst cases included for the TUNEL analysis, because the craniectomy was performed later than in the ICH + craniectomy 1-hour group, but before the worst cases were to die, which occurred in the ICH + craniectomy 24-hour group. Taken together, results of the present study showed that decompressive craniectomy was of significant benefit in terms of reduced mortality, better neurological outcome, and more favorable behavioral scores, when performed up to 24 hours after the initial ICH. Furthermore, the 3 different timings of craniectomy after ICH showed that the earlier the craniectomy, the better the result. The fact that ICH, which is associated with high rates of mortality and disability rates, lacks any effective treatment, suggests the wisdom of rapid implementation of this surgical treatment in clinical trials.
Disclosure This study was supported by grants from the Helsinki University Central Hospital (DS and TT), the University of Helsinki (TT), the Sigrid Jusélius Foundation (TT), the Maire Taponen Foundation (DS, UAR, and TT), the Alfred Kordelin Foundation (IM), and the Finnish Academy of Sciences (TT). The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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13. Piriyawat P, Morgenstern LB, Yawn DH, Hall CE, Grotta JC: Treatment of acute intracerebral hemorrhage with epsilon-aminocaproic acid: A pilot study. Neurocrit Care 1:47–51, 2004. 14. Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, Yong VW, Peeling J: Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 53:731–742, 2003. 15. Qureshi AI, Ali Z, Suri MF, Shuaib A, Baker G, Todd K, Guterman LR, Hopkins LN: Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: An in vivo microdialysis study. Crit Care Med 31:1482–1489, 2003. 16. Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ, Martin JE: Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8:711–713, 1997. 17. Strbian D, Durukan A, Tatlisumak T: Rodent models of hemorrhagic stroke. Curr Pharm Des 14:352–358, 2008. 18. Strbian D, Tatlisumak T, Ramadan UA, Lindsberg PJ: Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 27:795–802, 2007. 19. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W: Early decompressive surgery in malignant infarction of the middle cerebral artery: A pooled analysis of three randomised controlled trials. Lancet Neurol 6:215–222, 2007. 20. Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJ: Long-term prognosis after recovery from primary intracerebral hemorrhage. Neurology 59:205– 209, 2002. 21. Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT: Mechanisms of edema formation after intracerebral hemorrhage: Effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke 32:2932–2938, 2001.
Acknowledgment We thank Carol Norris, Ph.D., for editing the language. Ivan Marinkovic, M.D., and Daniel Strbian, M.D., Ph.D., contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.neurosurgery-online.com).
COMMENTS
M
arinkovic et al. examined the potential efficacy of craniectomy in the management of intracerebral hemorrhage (ICH) in an experimental rodent model. Animals were randomly allocated to craniectomy at 1, 6, or 24 hours or no craniectomy after a standard volume of ICH was created. Neurological, behavioral, and radiological outcomes were examined. In addition, terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive cells were counted. The authors demonstrated that rats undergoing craniectomy had improved outcomes, and those undergoing craniectomy earlier did better. This is a well-conducted study that highlights a potentially important area for further investigation. Spontaneous ICH remains an enormous clinical problem. Despite the negative results of the first Surgical Trial in Intracerebral Hemorrhage (STICH) trial, it is imperative that development of improved treatments for patients with spontaneous ICH continue. It would be interesting to see whether the size of the craniectomy matters. Illustrations from this study demonstrate significant brain herniation outside the craniectomy defect. Clearly, this preliminary work is promising, and the authors are encouraged to continue this line of investigation. R. Webster Crowley Ricky Medel Aaron S. Dumont Charlottesville, Virginia
www.neurosurgery-online.com
DECOMPRESSIVE CRANIECTOMY FOR INTRACEREBRAL HEMORRHAGE
SUPPLEMENTAL TABLE 1. Behavioral scoring scale Test or posture
Scoring scale
Startle reflex
0, none; 1, backward flick of pinnae; 2, jump 1 cm; 3, jump 1 cm
Positional passivity (held by tail)
0, no struggle; 1, slow struggling by hind limbs, occasional trunk curl; 2, strong struggling by hind limbs and rotation of the shoulder
Trunk curl (held by tail)
0, absent; 1, present
Trunk direction
1, left curl; 2, right curl; 3, left and right curl
Visual placing response
0, none; 1, upon nose contact; 2, upon vibrasse contact; 3, before vibrasse contact; 4, early vigorous extension
Forelimb extension and tension for right and left limbs separately
0, absent; 1, present
Forepaw grasping for right and left limbs separately
0, absent; 1, present
Grip strength for right and left limbs separately
0, none; 1, slight grip, semieffective; 2, moderate grip, effective; 3, active grip; 4, unusually effective
Smooth touch reflex for right and left limbs separately
0, weak; 1, flexible
Body position in viewing jar
0, completely flat; 1, lying on side; 2, lying prone; 3, sitting or standing; 4, rearing on hind legs; repeated vertical leaping
Spontaneous activity in viewing jar
0, none, resting; 1, casual scratching, grooming, slow movement; 2, vigorous scratching, grooming, moderate movement; 3, vigorous, rapid/dart movement; 4, extremely vigorous, rapid/dart movement
Head position in viewing jar
0, head down; 1, normal head position; 2, raised head
Forelimb support (when body position in jar 3)
0, none; 1, by left paw; 2, by right paw; 3, by both paws
Catatonia-like behavior in viewing jar
0, absent; 1, present
Forelimb abnormal position in jar
0, none; 1, left paw; 2, right paw; 3, both paws
Forelimb stereotypic in viewing jar
0, absent; 1, present
Head stereotypic in viewing jar
0, absent; 1, present
Stereotypic jaw-motion in viewing jar
0, absent; 1, present
Stereotypic rotation in viewing jar
0, absent; 1, present
Falling to the side in viewing jar
0, none; 1, animal falling down on the left side (from vertical position); 2, animal falling down on the right side
Posture abnormalities in viewing jar
Sum of 7 previous tests
Beam maneuver
0, active grip with hind limbs; 1, difficulty to grasp with hind limbs; 2, unable to grasp with hind limbs; 3, unable to lift hind limbs, falls within seconds; 4, falls immediately
Forepaw grasping on beam
0, absent; 1, by left forepaw; 2, by right forepaw; 3, by both
NEUROSURGERY
VOLUME 65 | NUMBER 4 | OCTOBER 2009 | ONL1
